A greater understanding of the molecular regulators of the immune and inflammatory responses will ultimately result in more effective immunotherapy. The chemokines (named for chemotactic cytokines) are a burgeoning family of such molecular regulators. They are secreted 8-10 kDa proteins that control the selective migration of leukocytes into inflammatory sites. Over 23,, chemokines have been identified and an ever growing number of chemokine receptors and highly related "orphan receptors" have been cloned. The complexity of the chemokine system suggests the chemokines have the capacity to precisely control the movement of leukocytes and lymphocytes. A greater understanding of these molecules, their receptors and their cellular targets is very likely to increase our understanding of human disease and offer clinicians and scientists the opportunity to control the movement of immune and inflammatory cells. This could lead to the therapeutic augmentation of the host response to tumor cells, infectious agents and vaccines. It may also allow the inhibition of a dysregulated host response in autoimmune, allergic and septic conditions. IP-10 (named for Induced Protein of 10 kDa) is a member of the chemokine family of proinflammatory cytokines and is secreted from a variety of cells in response to interferon-gamma and lipopolysaccharide stimulation. Constitutive expression of IP-l0 is restricted to thymic, splenic and lymph node stroma. However, IP-l0 expression is profoundly induced in a variety of tissues in inflammatory conditions, and its expression correlates with disease severity. IP-10 has an in vivo antitumor property that is dependent on T cells; in addition, IP-10 is anti-angiogenic. Our long term goals are to understand the role IP-10 plays in chronic inflammation and leukocyte trafficking in order to develop a novel antinflammatory agent. An additional goal is to determine if IP-10 will be a useful anticancer agent. To further these goals, we propose in Aim I to determine if direct injection of IP-10 into tumors will inhibit tumor growth and characterize the immune response stimulated by IP-10. In Aim 2 we will determine the mechanism by which IP-10 exerts its biological effects by identifying and characterizing its receptor on cells. In Aim 3 transgenic mouse models will be used to determine if constitutive expression of IP- 10 is sufficient to cause an inflammatory response or influence wound healing. Finally, in Aim 4 we will use gene-targeted mouse models and neutralizing anti-IP-10 monoclonal antibodies to determine if IP-10 plays a critical role in baseline leukocyte trafficking through the thymus, spleen and lymph nodes and in the pathophysiology of animal models of immune and inflammation diseases.